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Baader Bank ConferenceBad Ragaz
January 13, 2017
Safe HarbourThis presentation may include forward-looking statements that are based on our management’s beliefs and
assumptions and on information currently available to our management.
The inclusion of forward-looking statements should not be regarded as a representation by Cosmo that any
of its plans will be achieved. Actual results may differ materially from those set forth in this presentation due
to the risks and uncertainties inherent in Cosmo’s ability to develop and expand its business, successfully
complete development of its current product candidates and current and future collaborations for the
development and commercialization of its product candidates and reduce costs (including staff costs), the
market for drugs to treat IBD diseases, Cosmo’s anticipated future revenues, capital expenditures and
financial resources and other similar statements, may be "forward-looking" and as such involve risks and
uncertainties and risks related to the collaboration between Partners and Cosmo, including the potential for
delays in the development programs for LuMeBlue, and Zemcolo. No assurance can be given that the results
anticipated in such forward looking statements will occur. Actual events or results may differ materially from
Cosmo’s expectations due to factors which include, but are not limited to, increased competition, Cosmo’s
ability to finance expansion plans, the results of Cosmo’s research and development activities, the success
of Cosmo’s products, regulatory, legislative and judicial developments or changes in market and/or overall
economic conditions. Cosmo assumes no responsibility to update forward-looking statements or to adapt
them to future events or developments.
You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of
the date hereof, and Cosmo undertakes no obligation to revise or update this presentation.
3
Cosmo
The Tipping Point
4
Expanding the business from IBD to
a one-stop shop
for the colonoscopies mass market
The pipeline fulfills three key objectives
1. See more and see better
2. Remove lesions safer and better
3. Make the procedure more efficient
LuMeBlue
• Has successfully finished the phase III clinical trial
• Has shown statistical superiority versus white light HD
endoscopy
• Full data released November 29, 2016
• Allows Cosmo to enter a mass market
• Fulfills unmet needs of endoscopists
• Saves patients lives
• Has no competition
LuMeBlue
7
The mass market of colonoscopies
Every year:
- 15 million colonoscopies are performed in USA
- 17 million in Europe
- Potential for 60 million in RoW
SEE MORE and SEE BETTER1.
Colonoscopy: standard of care
What is the highest current standard of care in colonoscopies ?
High Definition White Light
Colonoscopy (“HDWL”)
Requires sophisticated HD equipment and it is used
in less than 20% of overall procedures
ISSUES
Even if using the best available tools, the Adenoma Detection Rate (“ADR”)
depends primarily on the subjective skill of the endoscopist.
3 462 colonoscopies18 endoscopists
3
ADR of
Individual
endoscopists
There is a need to
narrow the range
of ADR detection rates
HR 10
95% CI 1.4-87
1
Risk of interval cancer
by endoscopists
with high ADR
Risk of interval cancer
by endoscopists
with low ADR
The more patients
with adenoma are
detected….
The more cancer
is prevented
2
For each 1% increase in ADR:
3% decline in incidence
of interval CRC
5% decline in incidence
of fatal CRC
•For every 5% improvement in ADR:
•11% reduction in CRC incidence(95%CI, 10.3-11.9)
•13% reduction in CRC death(95%CI, 11.1-13.7)
•-3% cost due to saving in CRC treatment
Every year in USA:
- 149,000 CRC cases
- 50,000 CRC deaths
- 14$ billion
Chromoendoscopy
According to the ASGE-ESGE, chromoendoscopy “is the topical application of stains ordyes at the time of endoscopy in an effort to enhance tissue characterization,differentiation, or diagnosis»
Chromoendoscopy is recommended in IBD patients to
enhance detection of neoplasias
However it is used in less than 10% of overall procedures
ISSUES
dye needs to be prepared as a solutionselectively sprayed and washed out before mucosa readingrequires extensive cumbersome work and timerelies too much on subjectivity of the operator
15
Improving the subjective skill of
endoscopists in identifying dysplasia
Introducing
and going beyond HDWL
Significantly enhances ADR substantially
beyond HDWL and
FLAGSlesions in an previously unseen, unrivalled fashion
In ordinary trials, placebo is generally water and sugar
in our trial
Placebo is the highest
standard of care (HDWL)
and not only….… performed
In some of the top hospitals
by some of the top
endoscopist in the world
A one-of-a-kind trial
As an example
It is as taking the
performance of an Olympic
champion and making it
SIGNIFICANTLY BETTER
Increase his performance on 100m from 9.63s to 8.19s ?Can we do it ?
A one-of-a-kind trial
LuMeBlue is not a medical device or a tool but a fully fledged drug. The LuMeBlue trial is the first multicenter and multinational trial in colonoscopy with extremely stringent requirements therefore raising the odds and hurdles but also the overall reliability of the result.
A one-of-a-kind trial
Primary Endpoint
Proportion of subjects with at least one histologically proven Adenoma or Carcinoma
Main Secondary Endpoints
As of efficacy• False positive rate• Proportion of subjects with at least one
histologically proven Adenoma
As of safety• Adverse events• Renal and Liver function tests
A one-of-a-kind trial
Extraordinary homogeneity between FAS and PP, showing very few deviations and
therefore increasing overall data reliability.
PP shows the real efficacy of the treatment without major deviations. A large deviation
between FAS and PP may mean that results are influenced by factors external to the
protocol.
HDWL 200 mg 100 mg
Full Analysis Set (FAS) 479 485 241
Per Protocol (PP) 457 [95.4%] 455 [93.8%] 225 [93.4%]
Safety 479 488 241
A one-of-a-kind trial
LuMeBlue significantly enhances ADR in the full analysis set FAS
HDWL 200 mg
ADR 47.81% 56.29%
Relative risk increase* 17.7%
P-value 0.0099
Odds Ratio 1.41 [1.09, 1.81]
*Calculated as (ADRLuMeBlue 200 mg / ADRHDWL) - 1
The superiority of LuMeBlue False Positive Rate (FPR) versus HDWL was a criticalrequest from Agencies. Agencies wanted to make sure that LuMeBlue was not enticingthe endoscopist to remove lesions that would have subsequently not proven to beadenomas (diagnostically, a False Positive).
The Agencies, forecasting a higher number of False Positive (FP) in the patientstreated with LuMeBlue, allowed Cosmo to have a FPR versus HDWL in the range of+(15% / 35%).
LuMeBlue False Positive Rate is >> better than HDWL
LuMeBlue instead reversed the expectation and showed a significantly lower FPRthan HDWL, thus proving that with LuMeBlue the endoscopist:
• Finds less lesions, which
• Finds more lesions, which • Prove to be adenomas in a higher proportion
Whereas under HDWL the endoscopist:
• Prove to be adenomas in a lower proportion
LuMeBlue FPR is significantly better
than HDWL
FPR HDWL
29,7%
FPR LuMeBlue
23,3%
FP 83
FP 97
Total LuMeBlue pts : 485
Total HDWL pts : 479
Pts 326Pts 356
LuMeBlue decreases FPR by 14,4%vs HDWL
p-value: < 0,0001
LuMeBlue is clinically more relevant than
HDWL in the most important segment
of patients
If adenomas are detected during colonoscopy, the subject will be referred to a next
colonoscopy in a short time span ie 1-3 years
If no adenomas are detected during colonoscopy, the subject will be referred to a next
colonoscopy in 10 years
• missing an adenoma in this patient segment greatly increases the risk of an interval
cancer
• Missed adenomas will generally be flat and small
75/80% of patients have few lesions and experience less then 3 excisions
The Number of Excisions is one of the trial quality control parameters and has a very important meaning for adiagnostic treatment: lower the number of excisions, more difficult that a precancerous lesion could be positivelydetected in a patient.
The real value of a diagnostic is in this patients category.
LuMeBlue efficacy has high value diagnostic efficacy
ADR IN PTS WITH EXCISION ≤ 3
HDWL 35.9
LuMeBlue 45.3
RRI 26.2%
HDWL
Pts 362 Pts 376
45.3
35.9
RRI 26.2
ADR IN OVERALL PTS POPULATION
HDWL 47.81
LuMeBlue 56.29
RRI 17.7%
HDWL
Pts 485 Pts 479
56.29
47.81
RRI 17.7
LuMeBlue shows max diagnostic value increase
in the segment with 0 - 1 excision
ADR IN PTS WITH EXCISION 0 - 1
HDWL 18.94
LuMeBlue 26.18
RRI 38.2%
HDWL
Pts 233 Pts 264
26.2 18.9
RRI 38.2
ADR IN OVERALL PTS POPULATION
HDWL 47.81
LuMeBlue 56.29
RRI 17.7%
HDWL
Pts 485 Pts 479
56.29
47.81
RRI 17.7
LuMeBlue flags more subjects with histologically proven adenoma (excluding carcinoma) than HDWL
HDWL 200 mg
Pts with histologically proven
adenoma
220 268
Percentage overall population 45.93% 55.26%
Relative risk increase* 20.3%
P-value 0.0046
Odds Ratio 1.45
[1.13, 1.87]
Data from FAS
*Calculated as (ADRLuMeBlue 200 mg / ADRHDWL) - 1
LuMeBlue flags more subjects with non-polypoid lesions than HDWL
HDWL 200 mg Overall pts
Pts with non-polypoid lesions 168 213 273
Percentage overall population 35.07% 43.92% 56.29%
Relative risk increase* 25.2% 15.1%
P-value 0.0056 0.0099
Odds Ratio 1.45
[1.12, 1.88]
1.41
[1.09, 1.81]Data from FAS
*Calculated as (ADRLuMeBlue 200 mg / ADRHDWL) - 1
LuMeBlue flags more diminutive adenomas than HDWL
HDWL 200 mg
Patients with diminutive
adenomas
144 178
Percentage overall population 30.06% 36.70%
Relative risk increase* 22.1%
P-value 0.0342
Odds Ratio 1.35
[1.03, 1.76]
Data from FAS
*Calculated as (ADRLuMeBlue 200 mg / ADRHDWL) - 1
33
LuMeBlue
Development status
• Phase III completed, primaryendpoint “proportion of subjectswith at least one histologicallyproven Adenoma or Carcinoma”attained
Timing
• NDA Filing targeted for H1 2017
Business Development
• Discussions for RoW licensingongoing
2. REMOVE LESIONS
SAFER and BETTER
The current standard:a hand-made saline solution application
35
36
See the difference with Eleview ?
37
Eleview market potential from additional indications The tissues of the esophagus, stomach and duodenum are similar to those of the colon
Inspection of these conducted by Esophagogastroduodenoscopy (ECG)
Eleview can be used in all these tracts
As many ECGs are performed as colonoscopies, both in the US and Europe
During ECG, removal of tissues/polyps is frequently necessary and will require Eleview™ as per
below examples:
Stomach & duodenal polyps
• polyps requiring extraction are found
in around 0,7% of all procedures
Barretts Esophagus
• Caused by GERD, ~ 1,6% of population affected
• Requires an ECG every 3 years
• Tissue removal required in ~ 10% all cases
38
EleviewDevelopment status
• USA
approved
Marketing trials in four sites ongoing(speed and safety versus standard carein EMR)
• EU
Approved
Timing
• Targeted for launch in EU and USA in H12017
Business Development
• Licensing process in EU and RoWongoing
39
MAKE PROCEDURES
MORE EFFICIENT
REMIMAZOLAM
3.
40
Cost bundling in USA
Incentive to make procedures as fast as
possible
Make them cheaper by reducing use of
more costly personnel
Remimazolam
Procedural sedation is used in practically all colonoscopies in the USA
Market is split ~50%: 50% between propofol and midazolam
Targeted to save costs
Phase II b clinical trial demonstrate 6 min reduction in sedation time (faster onset and faster wake up) than midazolam allowing time for 1-2 additional colonoscopies per day
Propofol use will require presence/availability of an anaesthesist
One phase III completed for colonoscopies and one underway for bronchoscopy
Licensed in from PAION AG, who will pay for bronchoscopy trial, as an ideal marketing complement to LuMeBlue and Eleview
41
42
Cosmo’s pipeline goes beyond colonoscopies
After
and
expanding the unique position in GI
Project Rationale
Rifamycin SV is a well established, broad spectrum, lowtoxicity, semi-synthetic, antibiotic, approved and marketed forparenteral or topical use in some EU Countries for systemicor local infections control
Oral administration does not cause appreciable blood serumlevels in the systemic circulation:
this makes the drug an ideal agent for the treatment of localinfections control and in very common disorders ascomplementary to other drugs
Cosmo’s technology allows the antibiotic to be delivereddirectly into the colon, avoiding unwanted effects on bacterialflora living in the upper portions of the gastrointestinal tract
44
Site of action
Addresses the entire colon
MMX™ tablets
Most frequent health problem in travellers to developping countries
Often characterized by:
• Abdominal cramps
• Fecal urgency
• Nausea / Vomiting
• Fever
First indication: Travellers‘ Diarrhea
Consequences:
• immediate:
• Incapacitation
30 - 45% of patients for 12 - 21 h
[Steffen R et al. J Travel Med 2005;12:102-7]
• long–term:
• Irritable Bowel Syndrome (IBS)
11% of patients
[Okhuysen PC et al. Am Gastroenterol 2004;99:1774-8]
[Stermer E et al. Clin Infect Dis 2006;43:898-901]
45
46
Zemcolo: TD trialsPhase IIITwo pivotal clinical trials were required to support registration:
1 – US trial (superiority vs.
placebo)
A Phase 3, Multicenter, Randomized,
Double-Blind, Placebo-Controlled
Study to Evaluate the Efficacy and
Safety of Zemcolo for the Treatment
of Travelers’ Diarrhea.
2 – EU trial (noninferiority vs. Cypro)A randomised, double-blind, double-dummy,
multi-centre, comparative parallel-group
study to evaluate the efficacy and safety of
oral daily Zemcolo 400 mg b.i.d. vs.
Ciprofloxacin 500 mg b.i.d. in the treatment
of acute infectious diarrhoea in travellers
47
Zemcolo: TD trialsSuperiority vs placebo (Santarus)
Zemcolo shows a
TLUS clearly shorter
than placebo
Distributions of Time to Last Unformed Stool (ITT Population)
48
Zemcolo: TD trialsSuperiority vs placebo (Santarus)Outcome
This is the first ever
clinical trial in TD
against placebo where
the drug has clearly
shown a statistical
significance in clinical
treatment
Results from this well-
controlled Phase 3
study demonstrate a
favorable benefit-to-risk
profile for Zemcolo
400 mg administered
twice daily for 3 days
for patients with TD
49
Zemcolo: TD trialsNon-inferiority vs Cipro (standard of care) (Falk)OutcomeObjective:
To prove the non-inferiority of Zemcolo versus Ciprofloxacin for the treatment
of TD
Number of subjects:
Total enrolled: 835
Total completed: 814
Regions:
India, Guatemala, Ecuador, Peru, Mexico
Group A: 2 Zemcolo 200 mg tablets b.i.d.
Group B: 1 Ciprofloxacin 500 mg capsule b.i.d.
50
Zemcolo:Non-inferiority vs Cipro (standard of care) (Falk)Outcome
SantarusFalk
Ciprofloxacin
(FAS n=415)
Rifamycin SV-MMX
(FAS=420)
Placebo
(ITT n=65)
Rifamycin SV-MMX
(ITT n=199)
352 (84.8%) 357 (85%) 37 (56.9%) 162 (81.4%)
Zemcolo is as efficacious in treating TD patients as Cipro
and clearly superior to placebo
51
Non-inferiority of Zemcolo
vs Ciprofloxacin in main
microbial strain reduction
upon treatment
Zemcolo: TD trialsNon-inferiority vs Cipro (standard of care) (Falk)Outcome
ZEMCOLO CIPROFLOXACIN
Microbial Strain Baseline Final % reduct. Baseline Final % reduct.
# # # #
Giardia lamblia 45 19 57.8 34 15 55.9
Cryptosporidium parum 14 1 92.9 6 1 83.3
E. hystolytica 0 0 3 0 100.0
Shigella group 9 1 88.9 6 1 83.3
Salmonella group 5 0 100.0 11 0 100.0
Campylobacter Jejuni 16 2 87.5 24 7 70.8
Aeromonas 7 2 71.4 9 1 88.9
Plesiomonas 4 1 75.0 3 0 100.0
Heat stable toxin (ST) 127 55 56.7 128 53 58.6
Heat Labile toxin (LT) 16 6 62.5 11 7 36.4
Heat stable/lable toxin (SLT) 16 5 68.8 9 3 66.7
E. Coli enteroaggregative 99 22 77.8 89 23 74.2
Norovirus 9 1 88.9 12 4 66.7
totali 367 115 68.7 345 115 66.7
52
The study clearly showed non-inferiority of Zemcolo vs Ciprofloxacin in
terms of time to last unformed stool in TD
The secondary endpoints showed Zemcolo has similar efficacy vs
Ciprofloxacin
Zemcolo is a very safe drug
Zemcolo: TD trialsNon-inferiority vs Cipro (standard of care) (Falk)Outcome
53
Zemcolo: significant edge vs Cipro after
FDA issued a WARNING LETTER to CiproCiprofloxacin, because of its systemic absortion, has severe side effects and has just
received an FDA warning letter
Zemcolo, because of its colonic delivery, has no systemic absorption, thus practically
no side effects
54
Zemcolo: the way forward
1 – Travellers’ diarrhea is the simplest way to prove the antinfective property
in GI and requires short treatment
2 – Other indications will be advantageously pursued with this anti-infective,
anti-inflammatory drug: IBS and diverticulitis
3 – IBS and diverticulitis require formulations with different release profiles
that are under development. Zemcolo’s unique features offer clear advantages vs
standard of care
Note: IBS=Irritable Bowel Syndrome
Rifamycin Rifaximin
1IL1β 10 100 200 400 10 100 200 400
IL8 TNFα Rantes
Rifamycin Rifaximin
De
x
25
50
10
0
15
0
25
50
10
0
15
0
Rifamycin Rifaximin
De
x
25
50
10
0
15
0
25
50
10
0
15
0
Rifamycin Rifaximin
De
x
25
50
10
0
15
0
25
50
10
0
15
0
Rifamycin Rifaximin
De
x
1 10
50
10
0
1 10
50
10
0
Rifamycin Rifaximin
De
x
1 10
50
10
0
1 10
50
10
0
Rifamycin
Rifaximin
De x 1 10
50
10
0
1 10
50
10
0
Zemcolo: the way forward
Clear edge vs Xifaxan in anti-inflammatory propertiesIL6 TNFα Rantes
IL8
When corrected for number of viable
cells, it is shown that Zemcolo is a
more potent
anti-inflammatory agent than Xifaxan in
macrophages and colonic cell lines
55
Source: Cosmo - Report November 2016
μM
μM
μM
Monocytic
Cells
Macrophages
Colon
EpithelialCells
% inhibition of cytokines/
chemokines secretion
Zemcolo: the way ahead
clear edge vs Xifaxan in anti-inflammatory
properties
56
Source: Cosmo - Report September 2016
Based on the EC50 values, Rifamycin SV is 100 times more potent than
Rifampicin
Rifamycin SV is at least 1000 times more potent than Rifaximin at stimulating
PXR transcriptional activity in a cell line engineered to express a fusion human
PXR protein.
In terms of the maximum possible stimulation of PXR activity, rifaximin at 30
µM only activates up to 60% of the maximum activity with Rifamycin SV at 0.3
µM.
57
significantly reduces TLUS in TD
TLUS was significantly shorter in Zemcolo compared to placebo
showed non-inferiority vs Ciprofloxacin in terms of TLUS
secondary endpoints showed similar efficacy vs Ciprofloxacin
showed non-inferiority vs Xifaxan in TLUS and treatment success rates.
Zemcolo: wrap-up
58
In respect of potential competitors
Compared to Xifaxan, Zemcolo allows antibiotic to be delivered
directly to the colon, avoiding unwanted effects on the beneficial
saprophytic bacterial flora living in the upper portions of the
gastrointestinal tract
Compared to Ciprofloxacin, Zemcolo has no systemic absorption (very
important for resistance) and no warning box issues (Cipro’s use is
currently limited to really important infections), thus expanding
Zemcolo potential to address all patients currently prescribed with
Cipro in GI
Zemcolo is a New Chemical Entity (NCE) in the US
Zemcolo will, upon approval, enjoy 10 years of exclusivity in the USA
under the NCE/GAIN Act combined rules
Zemcolo: wrap-up
59
Zemcolo provides an effective and innovative treatment option for colonic
infections because
It is a broad spectrum, semi-synthetic, orally non-absorbable antibiotic
that can be used for the treatment of bacterial infections of the colon
such as traveler’s diarrhea
Antibiotics with negligible systemic absorption have the potential to
minimize systemic side effects and clinically important drug interactions
as well as potential sequelae from antibiotic use, including overgrowth of
pathogenic bacteria (ie, C. diff) and opportunistic infections (ie, Candida)
Zemcolo: wrap-up
60
ZemcoloDevelopment Plan
EU (licensed to Dr. Falk)
Travellers’ Diarrhoea
To be extended to: Uncomplicated Diverticulitis
Development Timeline: Phase II P.O.C. ongoing interimanalysis in January 17
US (Cosmo)
Travellers’ Diarrhoea
To be extended to: IBS D
Development Timeline: Phase II DR to start in Q3 16
Addressing the full value propositionCosmo will directly market its products in the US with most efficient structure
Research MarketingDevelopment Manufacturing Sales
The value chain
Research MarketingDevelopment Manufacturing SalesMarketing Sales
A specialty pharmaceutical company focused on commercializing best in class
products to treat gastrointestinal diseases
Introducing
Allowing Cosmo to capture the entire value chain
• Cosmo Pharmaceuticals NV has recently incorporated fully owned
Aries Pharmaceuticals Ltd, Dublin
• Aries Ltd is 100% holder of Aries Pharmaceuticals Inc., San Diego
• Aries Ltd will market in the US under a license and supply agreement
LuMeBlue, Eleview, Zemcolo and Remimazolam
• Aries Pharmaceuticals Inc. will act as a sales, marketing & distribution
company on behalf of Aries Pharmaceuticals Ltd
• Aries sub-holding group is crafted to allow replication of “equity for
product” strategy in respect of Cosmo Pharmaceuticals US pipeline
• Leveraging on existing fruitful relationships, Cosmo has hired a US
senior highly experienced management team located in San Diego
• Aries Inc. management team has a specific expertise in marketing and
distribution of GI drugs and pharmaceuticals products
• Aries Inc. management team is incentivized with a fully fledged ESOP
scheme with Aries Ltd shares
• Cosmo will consider listing Aries Ltd in a yet-to-be-selected Stock
Exchange when convenient
Introducing Aries Pharmaceuticals Inc. top management team
Tom Joyce – President & CEO
From 2004 to 2014 Vice President, Marketing and National Accounts at Santarus.
From 2014 to 2016 founder and partner of L.A.S. Partners, a health science
consulting company focused on providing commercial insight and strategy to
pharma and biotech companies. Has a B.A. in Psychology from the University of
Dayton
Jon Hee – Chief Commercial Officer
From 2004 to 2014 Vice President, Commercial Affairs at Santarus, where he
commercialized products for the gastrointestinal disease, diabetes and other
specialty markets. From 2014 to 2016 founder and partner at L.A.S. Partners
(see above). Has an M.B.A. from Harvard University and a B.S. in Chemical
Engineering from Stanford University
Blake Boland – Senior VP of Sales
From 2004 to 2014 Vice President of Sales at Santarus, where he developed and
led a national sales team, from company start-up, through all growth stages and
the company’s ultimate $2.6 billion sale in 2014. Consultant of several biotech
companies in commercial strategy, sales force structure, managed care, sales
and management training. Has a B.A. in Business Administration from Graceland
University and an M.B.A. from Rockhurst University.
Aries Inc. projected evolution of staff & salesforce according to preliminary marketing plans
Staffing Plan 2016 2017 2018 2019
Total 22 87 179 259
Thereof hired
salespersons
0 30 85 145
Additional salespersons
on contract (not included in
total)
0 30 85 85
Staffing may vary depending on launch timings
The Towers South
9276 Scranton Road
Suite 600
San Diego, California 92121
T: +1 (858) 202 6122
www.aries-pharma.com
Set-up of new offices and IT
infrastructure completed
Aries Inc. new offices in San
Diego, Scranton road
Information Contacts
•Number of shares: 14,418,983
•Listing: SIX Swiss exchange,
Main board
•ISIN: NL0011832936
•Alessandro Della Cha , CEO
•Luigi Moro, CSO
•Niall Donnelly, CFO
•Giuseppe Cipriano, COO
•Chris Tanner, Transactions & IR
Cosmo Pharmaceuticals
